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A low serum testosterone level at baseline was associated with higher risk for all-cause and cardiovascular disease (CVD) mortality, a meta-analysis of 11 prospective cohort studies found.

In age-adjusted analyses, men in the lowest quintile (8.46 nmol/L [244 ng/dL]) of total testosterone concentration had a higher risk for all-cause mortality (HR 1.09, 95% CI 1.01-1.17) and CVD mortality (HR 1.32, 95% CI 1.06-1.64) compared with men in the highest quintile, reported Bu Yeap, MBBS, PhD, of the University of Western Australia in Crawley, and colleagues.

In fully adjusted analyses that accounted for a host of other potential confounders, however, only men with testosterone concentrations below 7.4 nmol/L (213 ng/dL) had a higher risk for all-cause mortality, and only men with concentrations below 5.3 nmol/L (153 ng/dL) had a higher risk for CVD mortality, according to findings in the .

"This is, to our knowledge, the first [individual participant data meta-analysis] of major prospective cohort studies using mass spectrometry sex steroid assays, which clarifies previous inconsistent findings on the influence of sex hormones on key health outcomes in aging men," the researchers wrote.

Yeap elaborated on the significance of the findings in an email to MedPage Today. "These results provide insights on testosterone concentrations expected in healthy men, additional to information from laboratory reference ranges," he wrote.

The study also examined outcomes related to sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone (DHT), and estradiol concentrations. Key findings included the following:

• Lower SHBG was associated with lower all-cause and CVD mortality
• Concentrations of LH above 10 IU/L and estradiol below 5.1 pmol/L were linked with higher all-cause mortality
• The study found a U-shaped relationship with DHT and mortality risk

"The association of lower testosterone concentrations with higher all-cause mortality was present irrespective of luteinizing hormone concentrations," Yeap explained, "indicating that low testosterone was the main factor."

Furthermore, men with lower testosterone concentrations and normal or high SHBG had increased mortality risk, but those with lower testosterone concentrations and low SHBG had lower mortality risk, Yeap said. "This is consistent with the fact that men can have lower testosterone concentrations in the presence of low SHBG, without being hypogonadal."

In an accompanying the study, Bradley Anawalt, MD, of the University of Washington School of Medicine in Seattle, said a chief strength of the meta-analysis was its inclusion of studies that used mass spectrometry measurements.

"Mass spectrometry is considered the most accurate method of testosterone measurement and can also be used to measure DHT and estradiol accurately," Bradley said, "whereas widely available commercial immunoassays are inaccurate for measurement of these sex steroids in men, who typically have low serum concentrations of these two metabolites of testosterone."

The 11 studies in the meta-analysis were all prospective cohort studies of community-dwelling men who had sex steroids measured with mass spectrometry and were followed for at least 5 years. The median age of men in the studies ranged from 49 to 76. The researchers obtained individual participant data from nine of these studies, which included more than 20,000 men, and aggregate data statistics from the other two studies, which included more than 3,000 men.

The researchers modeled the testosterone data as a continuous variable, using restricted cubic splines. The primary outcomes were all-cause mortality, CVD death, and incident CVD events. Covariates for the fully adjusted analyses included age, body mass index, marital status, alcohol consumption, smoking, physical activity, hypertension, diabetes, creatinine concentration, ratio of total to high-density lipoprotein cholesterol, and lipid medication use.

The men in the studies were predominantly white and from Australia, Europe, and North America, so results should be confirmed in studies involving men of different ethnicities from other geographic regions, the researchers said. Another potential limitation of the meta-analysis was that sex hormones were assayed in different laboratories at different times.

Bradley concluded in his editorial, "Overall, these epidemiologic data support the hypothesis that hypogonadism is associated with higher cardiovascular and/or all-cause mortality. The data also support the free testosterone hypothesis that states that unbound testosterone is the active form of the hormone -- a hypothesis that is somewhat controversial."

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